Ehlers-Danlos syndrome (EDS) represents a heterogeneous group of generalized connective tissue disorders. The various forms of EDS all result from defects in collagen synthesis and/or processing. Collagen is the most abundant protein in the body and serves as a major building block of the extracellular matrix. Collagens are proteins that all contain three chains wound in a triple helix. There are 44 expressed collagen genes dispersed throughout the human genome and the protein products from these genes combine to form 28 different types of triple helical collagen. The major manifestations of EDS are skin fragility and hyperextensibility and joint hypermobility. To date, mutations in 8 genes involved in collagen synthesis or processing have been identified as causing the EDS phenotypes.
EDS types I and II are referred to as classical EDS.
Type I (gravis; also called the classic form) is the result of mutations in the collagen genes COL5A1 and COL5A2 and is inherited in an autosomal dominant manner. The characteristic clinical features of type I EDS are soft, velvety, and hyperextensible skin and easy bruising. The joints are quite hypermobile. Many patients with type I EDS have mitral valve prolapse. Trauma to the skin usually results in large gaping wounds that bleed less than expected. Repeated trauma to the knees, elbows and shins leads to pigmented scarring. In addition, the skin develops thin "cigarette-paper" scars as a result of trauma. The COL5A1 gene is located on chromosome 9q34.2–q34.3 and is composed of 67 exons that generate two alternatively spliced mRNAs encoding preproprotein isoform 1 (1838 amino acids) and preproprotein isoform 2 (1838 amino acids). Although both COL5A1 encoded isoforms are the same size, the isoform 2 preproprotein encoding mRNA contains an alternate exon in the 3' coding region. The COL5A2 gene is located on chromosome 2q14–q32 and is composed of 55 exons that encode a 1499 amino acid preproprotein.
Type II (mitis) is inherited in autosomal dominant fashion (rare events of autosomal recessive inheritance) and is the result of mutations in COL5A1. Because the mutations that cause type II are in the same gene that cause type I the symptoms are similar to those of type I but less severe.
Type III (familial hypermobility) is inherited in autosomal dominant fashion and is the result of mutations in the COL1A2 gene with rare occasions of COL3A1 mutations. Type III is characterized by marked hypermobility of both the large and small joints. The skin is soft but doesn't scar like in type I. The COL1A2 gene is located on chromosome 7q22.1 and is composed of 52 exons that encode three mRNAs that result from the use of alternative polyadenylation signals. All of these mRNAs encode the same 1366 amino acid preproprotein.
Type IV is the arterial type of EDS (also referred to as the vascular form). It is inherited in autosomal dominant fashion and is the result of mutations in the COL3A1 genes. The mutations alter the synthesis, structure and secretion of type III collagen. The characteristic features of this form of EDS are thin, translucent skin with visible veins which causes marked bruising. Patients with type IV are subject to arterial, uterine and bowel rupture. The COL3A1 gene is located on chromosome 2q31 and is composed of 51 exons that generate two mRNAs from the use of alternative polyadenylation signals. The COL3A1 encoded preproprotein is 1466 amino acids in length.
Type V is suspected to be an X-linked disorder with symptoms similar to those of type II. The gene defect(s) in type V has not yet been identified and there is some question as to whether EDS type V is indeed a distinct disease entity that should be classified as a type of EDS.
Type VI is the ocular type of EDS (also referred to as the kyphoscoliosis form). It is inherited in an autosomal recessive manner and results from deficiencies in lysyl hydroxylase due to mutations in the procollagen-lysine 2-oxoglutarate 5-dioxygenase 1 (PLOD1) gene. Patients have ocular fragility in addition to soft, velvety, hyperextensible skin and hypermobile joints. The PLOD1 gene is located on chromosome 1p36.22 and is composed of 21 exons that encode a protein of 727 amino acids.
Type VII comprises three distinct forms. Forms A and B are autosomal dominant disorders referred to as the arthrochalasis types (abnormal relaxation or flacidity of the joints) and form C is an autosomal recessive disorder referred to as the dermatosparaxis type (loss of skin strength and tearing). Type VIIA results from mutations in the COL1A1 gene that eliminates the N-proteinase cleavage site, type VIIB from mutations in the COL1A2 gene that eliminates the N-proteinase cleavage site and type VIIC that results from deficiencies in procollagen I N-proteinase activity (NPI). The NPI activity hydrolyzes the N-propeptide from type I, II, and V procollagens. The COL1A1 gene is located on chromosome 17q21.33 and is composed of 51 exons that generate two mRNAs via the use of alternative polyadenylation signals. The COL1A1 encoded preproprotein is 1464 amino acids in length. The NPI activity is a protein encoded by the ADAMTS2 gene (a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, 2). The ADAMTS2 gene is located on chromosome 5qter and is composed of 23 exons that generate two alterantively spliced mRNAs that give rise to two isoforms of the enzyme.
Type VIII is referred to as the periodontal type. This form of EDS can be distiguished from other EDS forms by the manifestation of severe gingival recession and periodontitis which results in premature loss of permanent teeth and resorption of alveolar bone by the third decade of life. There is no vascular or organ rupture phenotype in EDS type VIII. Skin anomalies in type VIII are similar to those found in EDS type II. The gene defect(s) in type VIII is not yet known.
Type IX is no longer considered a form of EDS and is now identified as occipital horn syndrome (OHS). This disorder was also referred to as X-linked cutis laxa, a term no longer used. OHS results from a defect in the same gene that is defective in Menkes disease, the copper-transporting ATPase, alpha subunit (ATP7A) gene. However, in the case of OHS the mutant ATP7A encoded protein retains some activity.
Type X is similar in phenotype to EDS type II but is not due to a defective collagen. The causes of EDS type X are defects in fibronectin. Fibronectins are a family of related adhesive glycoproteins. Fibronectins are important in connective tissue, where they cross-link to collagen. Type X EDS also has an associated platelet dysfunction due to the fibronectin abnormality. Fibronectin is encoded by the FN1 gene located on chromosome 2q34 and it is composed of 47 exons. The FN1 gene is subject to complex alternative splicing that results in the generation of at least 20 different mRNAs.